Osteoblast-targeted overexpression of PPARgamma inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice.

摘要

PPARgamma has critical role in the differentiation of mesenchymal stem cells into adipocytes while suppressing osteoblastic differentiation. We generated transgenic mice that overexpress PPARgamma specifically in osteoblasts under the control of a 2.3-kb procollagen type 1 promoter (Col.1-PPARgamma). Bone mineral density (BMD) of 6- to 14-week-old Col.1 - PPARgamma male mice was 8% to 10% lower than that of their wild-type littermates, whereas no difference was noticed in Col.1-PPARgamma female mice. Col.1-PPARgamma male mice exhibited decreased bone volume (45%), trabecular thickness (23%), and trabecular number (27%), with a reciprocal increase in trabecular spacing (51%). Dynamic histomorphometric analysis also revealed that bone-formation rate (42%) and mineral apposition rate (32%) were suppressed significantly in Col.1-PPARgamma male mice compared with their wild-type littermates. Interestingly, osteoclast number and surface also were decreased by 40% and 58%, respectively, in Col.1-PPARgamma male mice. In vitro whole-marrow culture for osteoclastogenesis also showed a significant decrease in osteoclast formation (approximately 35%) with the cells from Col.1-PPARgamma male mice, and OPG/RANKL ratio was reduced in stromal cells from Col.1-PPARgamma male mice. Although there was no significant difference in BMD in Col.1-PPARgamma female mice up to 30 weeks, bone loss was accelerated after ovariectomy compared with wild-type female mice (-3.9% versus -6.8% at 12 weeks after ovariectomy, p < .01), indicating that the effects of PPARgamma overexpression becomes more evident in an estrogen-deprived state in female mice. In conclusion, in vivo osteoblast-specific overexpression of PPARgamma negatively regulates bone mass in male mice and accelerates estrogen-deficiency-related bone loss in female mice. (c) 2011 American Society for Bone and Mineral Research.